Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13]3[C:19]4[C:20]([NH:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]6[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=6)=[C:27]([Cl:40])[CH:26]=5)=[N:21][CH:22]=[N:23][C:18]=4[S:17][C:14]=32)=[N:9]1)(=O)=O.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C(N(C(C)C)CC)(C)C>CC#N>[Cl:40][C:27]1[CH:26]=[C:25]([NH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]3[S:17][C:14]4[C:15]5[C:10]([CH2:11][CH2:12][C:13]=4[C:19]=23)=[N:9][N:8]([CH2:7][CH2:6][N:45]2[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]2)[CH:16]=5)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: CS(=O)(=O)OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CCN(CCn2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To 250 mL CH3CN were sequentially added 2-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl]ethyl methanesulfonate (5.80 g, 9.67 mmol), 1-methylpiperazine (3.22 mL, 29.0 mmol), and diisopropylethylamine (3.37 mL, 19.3 mmol). The opaque white suspension was stirred with heating to reflux, upon which the contents turn brown and homogeneous. After 15 h the mixture was removed from heating, and allowed to cool to rt. The contents were concentrated under reduced pressure to 10% volume, diluted with CH2Cl2 (150 mL), and washed with aq NH4Cl (50 mL). The aqueous layer was separated and extracted with CH2Cl2 (50 mL), and the combined organic layers then washed with sat. NaHCO3 (2×100 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The solid product was triturated from methanol and then recrystallized from ethanol to afford the final product (3.22 g, 55%) as an off-white solid. 1H-NMR (CD2Cl2) δ 1.98 (s, 3H), 2.30-2.50 (broad m, 8H), 2.68 (t, 2H), 2.98 (t, 2H), 3.25 (t, 2H), 4.08 (t, 2H), 5.07 (s, 2H), 6.93-7.00 (m, 3H), 7.14-7.20 (m, 2H), 7.25-7.39 (m, 2H), 7.75 (s, 1H), 8.31 (s, 1H); LCMS RT=3.15 min; [M+H]+=604.3.
Reaction SMILES: COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCNC=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.N1C=CC=CC=1.ClC(Cl)(O[C:51](=O)[O:52][C:53](Cl)(Cl)Cl)Cl.NC1C(F)=CC(C(N2CCN(CC)CC2)=O)=CC=1F.[CH2:78]([N:80]1[CH2:85][CH2:84][N:83]([C:86]([C:88]2[CH:93]=[C:92]([F:94])[C:91]([NH:95][C:96]([N:98]3[C:102]4[N:103]=[C:104]([N:132]5[CH2:137]COC[CH2:133]5)[N:105]=[C:106]([C:107]5[CH:108]=[N:109][C:110]([N:113](CC6C=CC(OC)=CC=6)CC6C=CC(OC)=CC=6)=[N:111][CH:112]=5)[C:101]=4[CH2:100][CH2:99]3)=[O:97])=[C:90]([F:138])[CH:89]=2)=[O:87])[CH2:82][CH2:81]1)[CH3:79].C(N[C@H](C(O)=O)CS)(=O)C>ClCCl.C(O)(C(F)(F)F)=O>[CH2:78]([N:80]1[CH2:85][CH2:84][N:83]([C:86]([C:88]2[CH:89]=[C:90]([F:138])[C:91]([NH:95][C:96]([N:98]3[C:102]4[N:103]=[C:104]([N:132]5[CH2:137][CH2:51][O:52][CH2:53][CH2:133]5)[N:105]=[C:106]([C:107]5[CH:112]=[N:111][C:110]([NH2:113])=[N:109][CH:108]=5)[C:101]=4[CH2:100][CH2:99]3)=[O:97])=[C:92]([F:94])[CH:93]=2)=[O:87])[CH2:82][CH2:81]1)[CH3:79]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN1CCN(C(=O)c2cc(F)c(NC(=O)N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c(F)c2)CC1
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: CCN1CCN(C(=O)c2cc(F)c(N)c(F)c2)CC1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1CCN(C(=O)c2cc(F)c(NC(=O)N3CCc4c(-c5cnc(N)nc5)nc(N5CCOCC5)nc43)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (2.50 g, 4.63 mmol) in dichloromethane (50 ml), pyridine (749 ml, 9.27 mmol) was added, and triphosgene (2.75 g, 9.27 mmol) was added under ice cooling. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. To this, dichloroethane (100 ml) was added, and (4-amino-3,5-difluoro-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (4.99 g, 18.5 mmol) obtained in Step D was added, followed by refluxing for 14 hours. The solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=50/1 to 10/1), to obtain a mixture of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [4-(4-ethyl-piperazine-1-carbonyl)-2,6-difluoro-phenyl]-amide and (4-amino-3,5-difluoro-phenyl)-(4-ethyl-piperazin-1-yl)-methanone. This was dissolved in TFA (40 ml), and N-acetylcysteine (1.13 g, 6.95 mmol) was added, followed by refluxing for 14 hours. The solvent was distilled off under reduced pressure. 5M-NaOH aqueous solution was added to adjust the pH to 8, and 500 ml of water was added, followed by extraction with dichloromethane (1 l×3). The solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=40/1 to 10/1), followed by further washing with methanol (100 ml), to obtain the desired compound as a yellow solid (1.31 g, 51%).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][CH:8]([O:11][C:12]1[CH:21]=[CH:20][C:15]([O:16][CH2:17][CH2:18][NH2:19])=[CH:14][CH:13]=1)[CH2:9][CH3:10].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:7][CH:8]([O:11][C:12]1[CH:21]=[CH:20][C:15]([O:16][CH2:17][CH2:18][NH:19][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:14][CH:13]=1)[CH2:9][CH3:10]
Reactant: O=C(Cl)C1CC1
Reactant: CCC(C)Oc1ccc(OCCN)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)Oc1ccc(OCCNC(=O)C2CC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
At 5° C., 3.4 g of cyclopropanecarboxylic chloride was dripped into a solution of 6.5 g of 2-[4-(1-methylprop-1-yloxy)-phenoxy]-ethylamine and 3.5 g of triethylamine in 100 ml of absolute methylene chloride. After the mixture had been stirred for 8 hours it was poured onto 200 g of ice/water and the resultant solution was adjusted to a pH of 2 with 2N aqueous hydrochloric acid. The aqueous phase was then extracted twice, each time with 50 ml of methylene chloride, and the combined organic phases were washed with saturated sodium carbonate solution and water, and dried over sodium sulfate. After removal of the solvent under reduced pressure and recrystallization from cyclohexane, there was obtained 6.4 g of N-{2-[4-(1-methylprop-1-yloxy)-phenoxy]-ethyl}-cyclopropanecarboxamide (compound no. 2); m.p.: 65°-68° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20].O[CH2:23][C@H:24]1[O:28][C:27](=O)[N:26]([C:30]2[CH:39]=[C:38]3[C:33]([CH:34]=[C:35]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]([F:50])([F:49])[F:48])[NH:36][C:37]3=[O:40])=[CH:32][CH:31]=2)[CH2:25]1.C[O:52]CCOCCOCCOCCOCCO>>[O:52]=[C:18]([O:17][CH2:16][CH:15]([CH2:23][C@@H:24]1[O:28][CH2:27][N:26]([C:30]2[CH:39]=[C:38]3[C:33]([CH:34]=[C:35]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]([F:48])([F:50])[F:49])[NH:36][C:37]3=[O:40])=[CH:32][CH:31]=2)[CH2:25]1)[O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:19]([O-:21])=[O:20].[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: COCCOCCOCCOCCOCCO
Reactant: O=C1O[C@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: COCCOCCOCCOCCOCCOCC(=O)O
Product: COCCOCCOCCOCCOC(COC(=O)C(=O)[O-])C[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)CO1

Procedure:
The title compound was synthesized by a condensation method similar to that of Step A of Example 3-1 using [2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)ethoxy]acetic acid instead of Boc-Sar-OH and 7-((S)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-13 instead of 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-14. However, [2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)ethoxy]acetic acid was synthesized by a method similar to that of Step A of Example 4-39 using pentaethylene glycol monomethyl ether instead of pentaethylene glycol monobenzyl ether.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1)([O-:5])=[O:4].[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl>CCOCC.O1CCCC1.C(O)C>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[CH:11][C:12](=[O:14])[CH2:13][C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:16]=1)([O-:5])=[O:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=O)CC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
Ethanol (9.5 ml) is added to a suspension of 60% sodium hydride (26.3 g) in anhydrous ether (750 ml), and thereto is added dropwise a mixture of p-nitrobenzalacetone (130 g), diethyl oxalate (99.4 g) and anhydrous tetrahydrofuran (550 ml) at 5°-10° C. with agitation. The mixture is agitated at room temperature for one hour, and thereto is added 10% hydrochloric acid (350 ml). The precipitated yellow solid is collected by filtration, washed with ether and then recrystallized from acetone to give ethyl 6-(4-nitrophenyl)-2,4-dioxo-hex-5-enoate (87.8 g). M.P. 148.5°-153.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.O[C:29]1[C:30]([CH3:39])=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:36]=[CH:37][CH:38]=[C:29]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[C:30]=1[CH3:39]
Reactant: COC(=O)c1cccc(O)c1C
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1cccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c1C

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and methyl 3-hydroxy-2-methylbenzoate (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White solid (9%). MS (Turbo Spray): m/z=539.2 [M+H].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26]1([CH2:32][CH2:33][C:34](Cl)=[O:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:34](=[O:35])[CH2:33][CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)CCc2ccccc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (99 mg, 0.40 mmol) and triethylamine (83 μL, 0.42 mmol) in methylene chloride (20 mL) was added dropwise 3-phenylpropionyl chloride (72 mg, 0.42 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 120 mg (61%) of the title compound as white crystals: mp 184-186° C.; [α]21D +6.5° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 374 (54, M+).
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=O)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14].Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[F:1][C:2]1[C:3](/[C:15](/[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:25]\[OH:26])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: Cc1ccncc1-c1ccnc(C(=O)c2ccc(F)cc2)c1F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccncc1-c1ccnc(/C(=N\O)c2ccc(F)cc2)c1F
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A solution of (3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl)(4-fluorophenyl)methanone (0.029 g, 0.093 mmol) and hydroxylamine hydrochloride (0.044 g, 0.636 mmol) in pyridine (Volume: 0.467 ml) was refluxed for 1.5 hr, allowed to cool to room temperature, and then concentrated in vacuo. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 80-100% EtOAc in hexanes over 12 min, tr=2 5 min) gave the title compound (22 mg, 0.068 mmol, 72.4% yield) as a yellow solid. ESI MS (M+H)+=326.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]3[CH:20]=[CH:21][N:22]=[C:10]23)=[C:4]([F:23])[CH:3]=1.[CH2:24](Br)[C:25]#[CH:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:7]([O:8][CH2:26][C:25]#[CH:24])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]3[CH:20]=[CH:21][N:22]=[C:10]23)=[C:4]([F:23])[CH:3]=1
Reactant: C#CCBr
Reactant: O=c1cc(C(F)(F)F)n2ccnc2n1-c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1Cl

Procedure:
A mixture of 8-(4-chloro-2-fluoro-5-hydroxyphenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (4.3 g), propargyl bromide (2.3 g), potassium carbonate (2.1 g) and acetonitrile (100 ml) was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure. The residue was added with water and extracted with ethyl acetate. The extract layer was washed with water and dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from diisopropyl ether to give the compound of interest (4.2 g) as a milk white crystal.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[O:6][C:5]=1[CH3:16])(=O)[CH3:2].Cl.[NH2:18][OH:19]>CCO.N1C=CC=CC=1>[CH3:16][C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:8]([CH3:9])[C:4]=1[C:1](=[N:18][OH:19])[CH3:2]
Reactant: NO
Reactant: CC(=O)c1c(C)oc(-c2ccncc2)c1C
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1c(C)oc(-c2ccncc2)c1C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a stirred solution of 3-acetyl-2,4-dimethyl-5-(4-pyridyl)furan (0.5 g, 2.33 mM) in EtOH (10 mL) and pyridine (2 mL) was added hydroxylamine hydrochloride (0.2 g, 2.79 mM) at room temperature. After stirring overnight, volatiles were removed by evaporation. Ethyl acetate (100 mL) and water (70 mL) were added, and partitioned. The organic layer was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The resulting solid was triturated to give the subtitle compound (0.45 g, 84% yield).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([O:11]C)[CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6].C[S-].[Na+]>CN(C)C(=O)C.O>[OH:2][C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6]
Reactant: COc1cc(OC)c(C=O)c([N+](=O)[O-])c1
Agent: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=Cc1c(O)cc(O)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
2,4-dimethoxy-6-nitro-benzaldehyde (135 mg, 0.638 mmol) and sodium methanethiolate (125 mg, 1.78 mmol) are dissolved in 4 ml of N,N-dimethylacetamide and heated at 80° C. for 26 h. The reaction mixture is diluted to 50 ml with water and extracted with dichloromethane. The aqueous layer is then acidified with 5% HCl and extracted again with dichloromethane. All of the organic layers are dried over Na2SO4, concentrated, and purified using silica gel chromatography (100% dichloromethane to 30% acetone in dichloromethane) to yield 2,4-dihydroxy-6-nitro-benzaldehyde.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[C:18](NC(NC3C=CC=C(C(F)(F)F)C=3)=O)[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([CH2:3][CH2:2][CH2:1][NH:7][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[CH:17]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2-c2ccccc2)cc1
Reactant: O=C=Nc1ccccc1
Product: NS(=O)(=O)c1ccc(-n2nc(CCCNC(=O)Nc3ccccc3)cc2-c2ccccc2)cc1
Yield: 90 %

Procedure:
The titled compound was prepared in 90% yield from phenyl isocyanate using the procedure detailed for compound 7. mp 171.0-172.1° C. 1H NMR (300 MHz, DMSO-d6): δ 8.43 (s, 1H), 7.79 (d, J=9 Hz, 2H), 7.47-7.36 (m, 9H), 7.29-7.16 (m, 4H), 6.87 (t, J=7 Hz, 1H), 6.57 (s, 1H), 6.23 (t, J=6 Hz, 1H), 3.25-3.14 (m, 2H), 2.69 (t, J=8 Hz, 2H), 1.92-1.78 (m, 2H). MS (ESI) m/z: 476.18 (M+H+). Anal. Calcd for C25H25N5O3S.0.3CH4O: C, 62.63; H, 5.44; N, 14.43. Found: C, 62.63; H, 5.34; N, 14.41.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([CH3:21])=[C:13]([Cl:20])[C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:15]1[C:14]2[C:13]([Cl:20])=[C:12]([CH3:21])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[N:2]=1
Reactant: CCOC(=O)c1c(N)sc(C)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cccnc1
Product: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1Cl

Procedure:
With the procedure of Example 477, the reaction of 3-cyanopyridine and 2-amino-4-chloro-5-methyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-3-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=O.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH2:7][N:12]1[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]1
Reactant: O=Cc1occc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2occc2Br)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
To a solution of 3-bromofuran-2-carbaldehyde (500 mg, 2.85 mmol) and tert-butyl piperazine-1-carboxylate (1.1 g, 5.71 mmol) in CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (1.2 g, 5.71 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (100 mL). The organic phase was washed with aqueous NaHCO3 and brine then dried (MgSO4), filtered and concentrated to dryness. The residue was purified by column chromatography (silica, 0-10% MeOH in CH2Cl2) to afford the sub-title compound (910 mg, 92%).
Reaction SMILES: CCCC[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:16]([OH:18])=[O:17].S(=O)(=O)(O)O.[CH3:24]O>>[C:16]([O:18][CH3:24])(=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]#[CH:5]
Reactant: CCCCCCCCCCCCCC#CC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: C#CCCCCCCCCCC(=O)OC
Temperature: 25 °C
Yield: 96 %

Procedure:
To a stirring solution of acetylenic acid 3 (37 g, 188 mmol) in 1.1 L of methanol was added 2.2 mL of concentrated sulfuric acid, and the resulting reaction mixture was heated under reflux for 16 h. Upon cooling to room temperature, the reaction mixture was concentrated to one third volume in vacuo, diluted with 1 L of 2:1 hexanes/diethyl ether, and washed with 2×50 mL of saturated aqueous sodium bicarbonate. The combined aqueous washes were further extracted with 2×150 mL of diethyl ether, treated with 50 mL of brine, combined with the previous organic extract and dried sodium sulfate. Concentration in vacuo gave a biphasic residue that was partitioned with 500 mL of hexanes and 50 mL of brine. The aqueous layer was further extracted with 2×50 mL of hexanes, the combined organic layers were dried over sodium sulfate, concentrated in vacuo, and vacuum dried to give methyl ester 4 (38.2 g, 96%) a golden-brown oil:
Reaction SMILES: [CH3:1][N:2]1[CH2:21][CH2:20][N:5]2[C:6]3[CH:19]=[CH:18][N:17]=[CH:16][C:7]=3[C:8](=O)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1.C(O)COCCO.[OH-].[K+].O.NN>CS(C)=O>[CH3:1][N:2]1[CH2:21][CH2:20][N:5]2[C:6]3[CH:19]=[CH:18][N:17]=[CH:16][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1
Reactant: CN1CCN2c3ccncc3C(=O)c3ccccc3C2C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: OCCOCCO
Solvent: O
Product: CN1CCN2c3ccncc3Cc3ccccc3C2C1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
800 mg (0.00285 mol) 2-methyl-10-oxo-1,2,3,4,10,14b-hexahydro-benzo[c]pyrazino[1,2-a]pyrido[3,4-f]azepine is added to a well-stirred suspension consisting of 4 ml di-ethylene glycol, 1 ml DMSO, 0.4 g KOH and 1 ml 80% hydrazine hydrate. The reaction is exothermic; the temperature of the reaction mixture is adjusted to 120° C and held there for 30 minutes. During this period hydrazine/water (0.8 ml) is distilled off, and the reaction temperature is then raised to 160° C for 2 hours. The reaction mixture is subsequently cooled, poured into water, and extracted with ether. After drying, and removing the solvent by evaporation, 685 mg (90%) 2-methyl-1,2,3,4,10,14b-hexahydro-benzo[c]pyrazino[1,2-a]pyrido[3,4-f]azepine is obtained as a light yellow oil.
Reaction SMILES: C1C2C(C[O:15][C:16]([CH2:18][S:19]([NH:22][N:23]3[CH2:27][CH:26]([C:28]4[CH:33]=[CH:32][C:31]([CH:34]5[CH2:36][CH2:35]5)=[CH:30][CH:29]=4)[N:25]([CH2:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=4)[C:24]3=[O:47])(=[O:21])=[O:20])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.CCCCCCC=CCCC>CN(C=O)C>[CH:34]1([C:31]2[CH:32]=[CH:33][C:28]([CH:26]3[CH2:27][N:23]([NH:22][S:19]([CH2:18][C:16]([OH:17])=[O:15])(=[O:21])=[O:20])[C:24](=[O:47])[N:25]3[CH2:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)=[CH:29][CH:30]=2)[CH2:36][CH2:35]1
Reactant: COc1ccc(CCN2C(=O)N(NS(=O)(=O)CC(=O)OCC3c4ccccc4-c4ccccc43)CC2c2ccc(C3CC3)cc2)cc1
Agent: CCCC=CCCCCCC
Solvent: CN(C)C=O
Product: COc1ccc(CCN2C(=O)N(NS(=O)(=O)CC(=O)O)CC2c2ccc(C3CC3)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of 1-[[(9H-fluoren-9-ylmethyloxy)carbonylmethyl]sulfonylamino]-3-[2-(4-methoxyphenyl)ethyl]-4-(4-cyclopropylphenyl)-2-imidazolidinone (2.0 g, 0.0031 mol) in DMF (15 mL) at room temperature is added 1,8-diazabycyclo[5.4.0]undec-7-ene (0.35 mL). The reaction is stirred for approximately one hour, diluted with ice-cold 0.1 N HCl and extracted with ethyl acetate. The organic phase is washed with brine, dried (sodium sulfate) and concentrated. The residue is warmed in approximately 20 mL of ether and diluted slowly with approximately 20 mL of hexanes. The liquid is decanted and the resulting material is dried under vacuum to afford 1.08 g of the desired compound. 1H NMR (CDCl3) δ 8.03 (bs, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.1 Hz, 2H), 7.05 (m, 2H), 6.84 (m, 2H), 4.51 (t, J=8.4 Hz, 1H), 4.30 (s, 2H), 4.01 (t, J=8.7, 1H), 3.81 (s, 3H), 3.66 (m, 1H), 3.51 (m, 1H), 2.95 (m, 1H), 2.64 (m, 1H), 1.93 (m, 1H), 1.02 (m, 2H), 0.74 (m, 2H). MS 652 (MH+). Anal. calcd. for C23H27N3O6S ¼C4H10O: C, 58.58; H, 6.04; N, 8.54. Found: C, 58.37; H, 6.01; N, 8.35.